Fine control of Wnt signaling is essential for various cellular and developmental processes. However, deregulated Wnt signaling leads to colorectal cancer (CRC). Thus, elucidating the regulatory mechanisms of Wnt signaling to allow for its targeted manipulation is critical in CRC treatment. Our long-term goal is (i) to unravel distinct molecular mechanisms that promote intestinal tumorigenesis and (ii) to develop therapeutic methods to counter CRC cell proliferation and metastasis. Previous Studies - In addition to our consistent interest in Wnt signaling in cancer and development, we recently revealed that PCNA-associated factor (PAF) hyperactivates Wnt signaling and promotes CRC cell proliferation, strongly implies that PAF promotes intestinal tumorigenesis. Despite biologic functions of PAF in controlling DNA repair and Wnt signaling, pathologic roles of PAF in cancer are undetermined. Significance - With efforts by biotechnology groups have produced only limited success to date, there is a critical need to develop novel approaches to block the Wnt pathway. One complication is that Wnt signaling is indispensable to tissue homeostasis and regeneration. Thus, the targeting of Wnt signaling regulators whose expression is specifically restricted to cancer provides an opportunity to minimize normal tissue damage. Importantly, PAF expression is significantly elevated in CRC, but not in normal tissues. Additionally, PAF knockout (KO) mice are viable. These evidences indicate potential therapeutic advantages of specifically inhibiting Wnt signaling through manipulating PAF, a Wnt signaling regulator we identified. Thus, our proposed study is necessary to determine whether PAF is a therapeutic target for CRC. Based on our previous studies and preliminary results, we hypothesize that PAF accelerates intestinal tumorigenesis via Wnt signaling and epigenetic gene regulation. To test our hypothesis, we will accomplish the following specific aims: Aim 1 to determine in vivo tumorigenic role of PAF, using our genetically engineered mouse models; Aim 2 to dissect PAF-mediated silencing mechanism of Wnt antagonist in CRC; Aim 3 to determine the mechanism of PAF upregulation in CRC.